PROJECT SUMMARY/ABSTRACT Three decades of research have shown a disproportionate prevalence of hypothyroidism (~25%) in chronic kidney disease (CKD) patients, including those receiving dialysis. While hypothyroidism has been associated with heightened cardiovascular (CV) morbidity and mortality in the general population, there had previously been a paucity of data on its prognostic implications in CKD. During the first 2 years of the parent K23 award, Dr. Connie Rhee (PI) has published pioneering studies showing that elevated thyrotropin (TSH) levels even within the normal range (>3.0mIU/L) are associated with higher mortality across multiple dialysis cohorts. Her seminal work showing a link between high-normal TSH levels and worse health-related quality of life (HRQOL) Short Form 36 (SF36) scores in dialysis patients also suggest that impaired HRQOL may be an under-recognized pathway to death. However, there remains considerable controversy as to 1) whether thyroid dysfunction is causally associated with adverse CV and patient-centered outcomes, 2) if elevated TSH levels represent hypothyroidism vs. non-thyroidal illness in CKD patients, and 3) the optimal TSH range associated with the greatest health benefit in dialysis patients. Furthermore, while United States Renal Data System data show that levothyroxine (L-T4) is one of the most commonly prescribed medications in pre-dialysis CKD and end-stage renal disease patients, little is known about its efficacy and safety in this population. These discoveries have motivated the present R03 application in which Dr. Rhee aims to conduct a double-blind, placebo-controlled pilot feasibility randomized controlled trial (RCT) of L-T4 administration over 12 weeks among 96 hemodialysis patients with high-normal or subclinical hypothyroid TSH levels who will be recruited from her parent NIH/NIDDK K23 study and the K24-sponsored ?Malnutrition, Diet, and Racial Disparities in CKD? cohort. Aim 1 will determine L-T4?s efficacy in achieving a target TSH range of 0.5- 3.0mIU/L (primary objective). Aim 2 will examine whether L-T4 treatment results in improvement of 1) HRQOL SF36 scores and 2) novel CV biomarkers of heart failure, endothelial function, and platelet activation, 3) without leading to increased protein catabolism ascertained by indices of protein-energy wasting (secondary objective). Findings from this pilot feasibility study will provide the framework for a future, large-scale multi- center RCT that 1) may uncover thyroid dysfunction as a novel, modifiable risk factor for CV disease and impaired HRQOL, and 2) will inform the management of the vast number of CKD patients affected by this prevalent endocrine-renal disorder. Moreover, support of the R03 award will allow Dr. Rhee to accelerate her progress towards independence by providing her with 1) practical experience in the implementation of a pilot feasibility RCT, 2) hands-on exposure to translational medicine and laboratory platforms through CV biomarker testing, and 3) extension of the rich multi-disciplinary collaborations she has developed during the parent K23 award period.